Ryanodine and dehydroryanodine are represented by the following formula: ##STR1## wherein, when R is H and Z is C(H)CH.sub.3, ryanodine is represented, and when R is H and Z is C.dbd.CH.sub.2, dehydroryanodine is represented.
Ryanodine (Merck Index number 8065-9th Edition) and dehydroryanodine are insecticidal alkaloids derived from the stem and roots of the plant Ryania speciosa Vahl, native to Trinidad. Crude extracts of the plant contain upwards of 25 alkaloids. Ryanodine is 700 times more potent as an insecticide than the crude alkaloidal extract, and was first isolated by Rogers et al, J.Am Chem Soc. 70 3086 (1948). Its structure was determined by Wiesner et al, Tetrahedron Letters 1967 221. The purification and structure of dehydroryanodine are disclosed in publications by Waterhouse et al, J. Chem Soc. Chem. Commun., 1984 1265 and J.Chem Soc., Perkin Trans 2 1985 1011. A later paper by the same group published in J. Med. Chem., 30 710 (1987), discloses a number of derivatives of ryanodine as well as three new alkaloids. Ruest et al, Can. J. Chem., 63 2840 (1985) disclose a number of other Ryania speciosa alkaloids. The above publications disclose one derivatizate of the 10.sub.eq -hydroxyl, the acetate.
The pharmacology of ryanodine is summarized in an article by Jenden and Fairhurst, Pharmacological Reviews 21 1 (1969). In addition to its insecticidal properties, ryanodine also has a profound effect on mammalian skeletal muscle (irreversible confracture) and a negative inotropic effect on mammalian cardiac muscle. Jenden and Fairhurst conclude that ryanodine specifically interferes with vertebrate skeletal muscle relaxation, an activity believed to be effected by sequestration of Ca.sup.++ ions by the sarcoplasmic reticulum. Ryanodine has been shown to obstruct active uptake of Ca.sup.++ by skeletal muscle sarcoplasmic reticulum (SR). It therefore follows that ryanodine interferes with intracellular Ca.sup.++ transport mechanisms and inhibits the normal lowering of the sarcoplasmic Ca.sup.++ concentration that effects relaxation. In cardiac muscle, ryanodine's inhibition of SR Ca.sup.++ uptake results in a depletion of SR Ca.sup.++ stores with a subsequent loss of contractility. Ryanodine is also postulated to have other pharmacologic actions in smooth muscle and in systems free of functional remnants of the SR such as nervous and hepatic tissue. Here again, these effects are also Ca.sup.++ dependent.
Specific information about the mode of action of ryanodine on cardiac SR was published by Sutko, Willerson, Besch et al J.P.E.T. 209 37 and Jones, Besch, Sutko et al id 40 (1979). More specific information is to be found in a paper by Inui et al, J.B.C. 262 15637 (1987). The authors found that ryanodine reacts with Ca.sup.++ release channels localized in the terminal cisternae of the SR. The ryanodine receptor from cardiac SR used by the authors was purified by selective chromatography.